The present invention relates to a pharmaceutical composition containing hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and/or ethylcellulose (EC) as disintegrants.
It also relates to tablets composed of this composition.
A final object of the invention is a process for producing such tablets.
Various types of disintegrants are used in pharmaceutical compositions, at varying doses, depending on the effect sought for. The concentration of the disintegrant in the composition may be selected so as to achieve a more or less fast release of the active ingredient contained in the composition.
Cellulose derivatives are used as excipients: among these are the hydroxypropylcelluloses (HPC), the hydroxypropylmethylcelluloses (HPMC), and the ethylcelluloses (EC). There are two derivatives of the HPC, one highly substituted (H-HPC), and the other weakly substituted (L-HPC).
Thus, according to the monograph of the American Pharmacopoeia is (USP 23/NF 18), L-HPC has a substitution level of less than 10%. It is known for its qualities as a binder and a disintegrant.
H-HPC has a substitution level of the cellulose by hydroxypropoxy units of about 80%, as defined by the American Pharmacopoeia (USP 23/NF 18). This compound is known for its qualities as a binder.
L-HPC, although having satisfactory disintegrant properties, is a poor binding agent, whose unit cost is significantly higher than that of HPMC and H-HPC.
The problem at the root of the invention is to find agents whose general properties (toxicity, etc.) render them suitable for use in pharmaceutical compositions, and with binding and disintegrant properties presenting a compromise enabling them to form a discontinuous, or lacunary, matrix, making an effective disintegration possible, while retaining cohesion between the different constituents of the composition.
Such agents must in addition be active in small quantities, so that the active ingredients in the formulations remain the majority components.
The applicant has thus endeavored to find such an agent.
The applicant has unexpectedly demonstrated disintegrant properties of derivatives of H-HPC, HPMC and ethylcellulose (EC).
The present invention, in its most general form, thus concerns the use of hydroxypropylmethylcellulose (HPMC), highly substituted hydroxypropylcellulose (HPC), and/or ethylcellulose (EC) as disintegrants in pharmaceutical compositions.
For the purposes of the present invention, highly substituted hydroxypropylcellulose should be understood as any cellulose containing a minimum of 50%, preferably a minimum of 65%, and preferably a minimum of 75% of substitution by hydroxypropoxy groups.
Hydroxypropylmethylcellulose should be understood as any cellulose substituted by hydroxypropyl and methoxy groups, whatever the percentage of substitution. However, such a hydroxypropylmethylcellulose advantageously has a substitution level by hydroxypropoxy groups of between about 2 and 45%, and by methoxy groups of between about 10 and 40%.
The object of the invention is more precisely a pharmaceutical composition comprising at least one active ingredient and hydroxypropylmethylcellulose (HPMC), highly substituted hydroxypropylcellulose (HPC), and/or ethylcellulose (EC) as disintegrants, in quantities less than 15% by weight of the composition and in a form providing a disintegrant effect while avoiding the formation of a continuous matrix.
This absence, or quasi-absence, of a continuous matrix is demonstrated by the release profiles of the active ingredients. It may also be observed by cryofracture or by scanning electron microscopy.
Such a composition advantageously contains less than about 10% by weight of HPMC, highly substituted HPC and/or ethylcellulose, and preferably between about 1.5 and 7% by weight of HPMC, highly substituted HPC and/or ethylcellulose.
The use of hydroxypropylcellulose, hydroxypropylmethylcellulose or ethylcellulose as disintegrants allows the production of compositions, and in particular tablets, containing at least about 80%, preferably at least about 85% and even more preferably at least about 90% by weight of the active ingredients in the composition.
Such active ingredients may be any pharmacologically active molecules to be released into a liquid, either extracorporeal or intracorporeal.
Such an active ingredient is preferably paracetamol or diclofenac.
The compositions according to the present invention enable modulation of the kinetics of release of the active ingredient, as a function of the mode of incorporation and/or the concentration and/or the particle size of H-HPC, HPMC or EC.
The applicant has unexpectedly shown that the disintegrant power of H-HPC, HPMC and EC is inversely proportional to their particle size. The compositions according to the present invention advantageously contain H-HPC, HPMC or EC in micronized form. These cellulose derivatives are preferably present in the form of powders with an average diameter of less than about 50 xcexcm. Such a diameter allows the total quantity of these cellulose derivatives to be reduced to 2.5%.
The composition may in addition contain at least one binding agent, so as to maintain the bond between the excipients constituting the composition. The binding agent may in particular be polyvinylpyrrolidone (PVP) or methyl polymethacrylate.
It may also be HPMC, H-HPC or EC in a form enabling an binding effect to be obtained, in other words added during the manufacture of the composition in solution form, and not micronized.
Although the present invention preferentially relates to tablets, the composition according to the present invention may also be in the form of powder, granules, or any other pharmaceutical form, selected as a function of the active ingredient which it is desired to administer, and of the mode of administration.
A person skilled in the art could determine, for each active ingredient, the appropriate quantities of highly substituted hydroxypropylcellulose, hydroxypropylmethylcellulose and/or ethylcellulose, in particular by using the dissolution tests described in the European Pharmacopoeia (1997, Pharmotechnical Methods, p. 127 to 130). These tests are performed by placing a granule or a tablet containing the active ingredient in a blade, bucket or continuous flow apparatus and observing the kinetics of release of the active ingredient. The skilled person could thus simply and reliably determine the quantities of highly substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and/or ethylcellulose and adjust the release (immediate or sustained) depending on the therapeutical needs.
These granules or tablets preferably comprise at least two phases.
According to a first embodiment, the active ingredients and H-HPC, HPMC and/or EC are comprised in the same phase.
They may however, according to a second embodiment, be comprised in two phases.
According to a third embodiment, the active ingredients and H-HPC, HPMC and/or EC are present in different phases.
According to a particularly advantageous embodiment of the present invention, the granules or tablets comprise two cores, the first or inner core, composed of a composition according to the present invention and comprising a certain quantity of one or more active ingredients.
The outer core comprises at least an effective quantity of one or more active ingredients and at least one compound with a strong disintegrant effect, but is composed of a composition different from that which is the object of the present invention. Such a composition allows immediate release of the active ingredients which it contains.
Such an embodiment of the present invention is particularly advantageous since it allows immediate release of a high dose of the active ingredient by dissolution of the outer core, and then release in delayed fashion of the active ingredient(s) contained in the inner core.
The inner core may itself be composed of two phases, inner and outer, of a composition according to the present invention.
Such an embodiment of the present invention is advantageously used with paracetamol as active ingredient.
The granules or tablets according to the present invention may be obtained by techniques known to a person skilled in the art, by granulation by dry or wet methods, or by direct compression for the tablets.
The granules may in particular be packaged into capsules, or into sachets.
According to a first method, the active ingredient(s) is (are) mixed in the inner phase with a binding agent in aqueous or organic solution, for example polyvinylpyrrolidone derivatives or cellulose derivatives such as HPMC or ethylcellulose. The HPMC, H-HPC or EC are added to the outer phase with a lubricant, for example magnesium stearate.
According to a second method, the active ingredient is mixed in the inner phase with HPMC or H-HPC or EC and a binding agent, for example PVP. These are mixed until a homogenous mixture is obtained. A binding solution is added and the mixture is then granulated. To the inner granule is added a lubricant as outer phase, for example magnesium stearate. The resulting composition then passes to the compression stage.
According to a third method, the active ingredient is mixed with H-HPC, HPMC or EC and an excipient in current use for direct compression such as lactose, starch or microcrystalline cellulose. A lubricant is added and the mixture is compressed.
In general, a person skilled in the art could refer to the general manual xe2x80x9cAbrxc3xa9gxc3xa9 de pharmacie galxc3xa9niquexe2x80x9d, Le HIR, Editions Masson, for the application of the present invention, and particularly for the preparation of compositions.